A5089318759- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Glycosylation and Glycoproteins Research
- Radiopharmaceutical Chemistry and Applications
- Peptidase Inhibition and Analysis
- Cancer therapeutics and mechanisms
- Cancer Treatment and Pharmacology
- CAR-T cell therapy research
- Cell Adhesion Molecules Research
- Click Chemistry and Applications
- Carbohydrate Chemistry and Synthesis
- Chemical Synthesis and Analysis
- Toxin Mechanisms and Immunotoxins
- Seaweed-derived Bioactive Compounds
- Biochemical and Molecular Research
- Lymphoma Diagnosis and Treatment
- Synthesis and Biological Evaluation
- Cancer Research and Treatments
- Protein purification and stability
- Natural product bioactivities and synthesis
- Biopolymer Synthesis and Applications
- Protein Hydrolysis and Bioactive Peptides
- Galectins and Cancer Biology
- Multiple Myeloma Research and Treatments
- Chronic Lymphocytic Leukemia Research
Seagen (United States)
2015-2024
Pfizer (United States)
2024
Seagen (Canada)
2007-2016
OncoGenex Pharmaceuticals (United States)
1988-2015
University of Washington Bothell
2011
University of Illinois System
2011
Korea Institute of Science and Technology
2010
Seoul National University
2010
RTI International
2009
North Carolina Central University
2009
An antibody-drug conjugate consisting of monomethyl auristatin E (MMAE) conjugated to the anti-CD30 monoclonal antibody (mAb) cAC10, with eight drug moieties per mAb, was previously shown have potent cytotoxic activity against CD30(+) malignant cells. To determine effect loading on therapeutic potential, we assessed cAC10 conjugates containing different drug-mAb ratios in vitro and vivo.Coupling MMAE cysteines that comprise interchain disulfides created an population, which purified using...
We have previously shown that antibody-drug conjugates (ADCs) consisting of cAC10 (anti-CD30) linked to the antimitotic agent monomethylauristatin E (MMAE) lead potent in vitro and vivo activities against antigen positive tumor models. MMAF is a new auristatin derivative with charged C-terminal phenylalanine residue attenuates its cytotoxic activity compared uncharged counterpart, MMAE, most likely due impaired intracellular access. In cytotoxicity studies indicated...
The linker component of antibody-drug conjugates (ADC) is a key feature in developing optimized therapeutic agents that are highly active at well tolerated doses. For maximal intratumoral drug delivery, linkers required stable the systemic circulation, yet allow for efficient release target site. In this respect, amide bond-based technologies constitute technological advancement, since half-lives circulation ( t 1/2 approximately 7 days) much longer than earlier generation break down within...
SGN-35 is an antibody-drug conjugate (ADC) containing the potent antimitotic drug, monomethylauristatin E (MMAE), linked to anti-CD30 monoclonal antibody, cAC10. As previously shown, treatment regresses and cures established Hodgkin lymphoma anaplastic large cell xenografts. Recently, ADC has been shown possess pronounced activity in clinical trials. Here, we investigate molecular basis for activities of by determining extent targeted intracellular drug release retention, bystander...
Nanobodies are the smallest fragments of naturally occurring single-domain antibodies that have evolved to be fully functional in absence a light chain. strictly monomeric, very stable, and highly soluble entities. We identified nanobody with subnanomolar affinity for human tumor-associated carcinoembryonic antigen. This was conjugated Enterobacter cloacae beta-lactamase, its site-selective anticancer prodrug activation capacity evaluated. The conjugate readily purified high yields without...
Site-specific conjugation of small molecules and enzymes to monoclonal antibodies has broad utility in the formation conjugates for therapeutic, diagnostic, or structural applications. Precise control over location would yield highly homogeneous materials that could have improved biological properties. We describe first time chemical reduction oxidation methods lead preferential cleavage particular antibody interchain disulfides using anti-CD30 IgG1 cAC10. Alkylation resulting cAC10 cysteine...
A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, engineered at position 239 of heavy chains. The h1F6239C-PBD conjugation strategy proved be superior cysteine conjugation, affording an antibody-drug conjugate (ADC) high uniformity in drug-loading and low levels aggregation. In vitro cytotoxicity experiments demonstrated...
The chimeric anti-CD30 monoclonal antibody cAC10, linked to the antimitotic agents monomethyl auristatin E (MMAE) or F (MMAF), produces potent and highly CD30-selective anti-tumor activity in vitro vivo. These drugs are appended via a valine-citrulline (vc) dipeptide linkage designed for high stability serum conditional cleavage putative release of fully active by lysosomal cathepsins. To characterize biochemical processes leading effective drug delivery, we examined intracellular...
Effective antibody-drug conjugates (ADC) combine high drug-linker stability in circulation and efficient intratumoral release of drug. Conjugation monomethyl auristatin E (MMAE) to the anti-CD30 monoclonal antibody (mAb), cAC10, produced a selective potent ADC against CD30(+) anaplastic large cell lymphoma Hodgkin's disease models. This ADC, cAC10-valine-citrulline-MMAE, uses protease-sensitive dipeptide linker designed MMAE by lysosomal cathepsin B target cells but maintain stable linkage...
Antigen variation is a successful defense system adopted by several infectious agents to evade the host immune response. The principle of this strategy in African trypanosome paradigm involves dense packing variant surface glycoproteins (VSG) exposing only highly variable and immuno-dominant epitopes system, whereas conserved become inaccessible for large molecules. Reducing size binders that target conserved, less-immunogenic, cryptic VSG forms an obvious solution combat these parasites....
Two anti-tumor monoclonal antibodies, L6 (anticarcinoma) and 1F5 (anti-B lymphoma), were covalently linked to alkaline phosphatase (AP), forming conjugates that could bind the surface of antigen-positive tumor cells. The capable converting a relatively noncytotoxic prodrug, etoposide phosphate (EP), into etoposide--a drug with significant antitumor activity. In vitro studies human colon carcinoma cell line, H3347, demonstrated while EP was less toxic than by factor greater 100, it equally...
Abstract PURPOSE: Advanced melanoma is a highly drug-refractory neoplasm representing significant unmet medical need. We sought to identify melanoma-associated cell surface molecules and develop as well preclinically test immunotherapeutic reagents designed exploit such targets. EXPERIMENTAL DESIGN AND RESULTS: By transcript profiling, we identified glycoprotein NMB (GPNMB) gene that expressed by most metastatic samples examined. GPNMB predicted be transmembrane protein, thus making it...